Several naturally-occurring alkaloids obtainable from Vinca rosea have been found active in the treatment of experimental malignancies in animals. Among these are leurosine (U.S. Pat. No. 3,379,057), vincaleukoblastine (vinblastine or VLB) (U.S. Pat. No. 3,097,137), leurosidine (vinrosidine) and leurocristine (VCR or vincristine) (both in U.S. Pat. No. 3,205,220). Two of these alkaloids, VLB and vincristine, are now marketed as drugs for the treatment of malignancies, particularly the leukemias and related diseases, in humans. Of these marketed compounds, vincristine is a most active and useful agent in the treatment of leukemias but is also the least abundant of the anti-neoplastic alkaloids of Vinca rosea.
Other dimeric indole alkaloids which have been isolated in small quantities from Vinca rosea, but which are less active antimitotically than VLB and vincristine, include leurocolombine, vincadioline, leuroformine, isoleurosine (deoxy VLB "B") and vincathicine -- see Svoboda and Barnes, J. Pharm. Sec., 53, 1227 (1964). Vincathicine is not as active in treating experimental malignancies in animals as leurocristine or VLB. However, the compound is much less toxic than either of the two more potent alkaloids and there is thus a more favorable therapeutic ratio available in its use. Vincathicine was obtained originally by Svoboda and Barnes (loc. cit.) in an extremely small quantity -- 7.8 grams of sulfate from 3659 grams of the chloroform eluate of postleurocristine material from the B fraction isolated from a benzene extract of leaf.
It is an object of this invention to provide a process for the partial synthesis of vincathicine from a readily available alkaloid and thus to obtain sufficient vincathicine not only for further studies of the use of the compound in the treatment of malignancies in animals, but also as a starting material for the preparation of more active anti-mitotic derivatives.